Spinal Muscular Atrophy (SMA) is a recessive neurodegenerative disease characterized by the selective loss of spinal motor neurons'. SMA is caused by mutation of the Survival-of-Motor-Neuron 1 (SMN1) gene2 and deficiency of the survival motor neuron (SMN) protein expression. All patients retain one or more copies of the SMN2 gene, which modulates the disease severity by producing a small amount of full-length SMN transcripts and consequently of stable SMN protein3. Since SMA is caused by insufficient amounts of SMN protein, a major aim of SMA therapeutics strategy is to increase SMN protein levels by activating SMN2 gene expression. However, to date there is no available therapy for SMA, which represents the leading genetic cause of death in childhood.
The mode of action of therapeutic molecules for the treatment of SMA may include the increase of SMN expression particularly in motor neurons through activating the SMN2 promoter, increasing exon-7 inclusion in SMN transcripts, or extending the half-life of SMN mRNA or protein.
It may also include the promotion of motor neuron survival through the activation of anti-apoptotic pathways. Over the years, a number of groups have identified SMN2 gene-inducing compounds using cultured fibroblasts derived from SMA patients, and which benefits were often further tested in vivo in SMA mouse models5. Among those, SMN inducer compounds were identified based on their supposed ability to increase general gene expression, such as histone deacetylase inhibitors6, 7, 8, or by high throughput screenings, such as quinazoline derivatives9, 10. Unfortunately, to date, many of these compounds were disappointing in clinical trials with no substantial clinical benefit demonstrated11, 12, 13. Ultimately, none of these compounds provide efficient anti-apoptotic potential for motor neurons.
One promising, as yet unexplored, therapeutic development for SMA could involve the pharmacological correction of molecular mechanisms, specifically altered in SMA neuromuscular system, potentially capable of modulating either SMN expression, or motor-neuron survival or both.
However, there is still a need to understand the molecular pathways involved in the modulation of SMN expression or motor-neuron survival and identify efficient strategies for treating SMA.
Constitutively down-regulated in mouse SMA spinal cord, the AKT/CREB pathway is able to remarkably alleviate SMA symptoms in mice as long as it is reactivated14. In very severe SMA-like mice15, the reactivation of AKT/CREB pathway by NMDA resulted in an increased in the total amount of SMN transcripts in the SMA spinal cord without modifying its splicing pattern suggesting a SMN2 gene regulation at the transcriptional level14. Furthermore, considered as a common and powerful antiapoptotic pathway16 notably for spinal motor neurons17, the AKT/CREB pathway activation likely represents an important clue for motor neuron resistance to cell death in SMA spinal cord. Thus, identifying therapeutic agents that could lead to the reactivation of the AKT/CREB pathway in SMA spinal cord has been suggested as a possible approach for treating SMA.
International Patent Publication No. WO2010/148249 (Isis Pharmaceuticals, Genzyme Corp, Cold Spring Harbor Laboratory) describes methods and compositions for modulating splicing of SMN2 mRNA in a subject, for the treatment of spinal muscular atrophy.
Interestingly, the activation profile of another major intracellular signaling pathway in neurons18, namely the ERK1/2 signaling pathway, was in opposite contrast to that of AKT in SMA spinal cord. Constitutively over-activated in the spinal cord of two different severe mouse models of SMA, characterized by a weak SMN expression, ERK1/2 was inhibited when AKT is reactivated and this change in ERK/AKT activation balance correlated with an increase in SMN expression14. However, these data failed to show any direct link between a modulation of ERK 1/2 signaling pathway and SMN2 gene regulation.
ERK inhibitors, such as Selumetinib have been described in the Art for their use in treating cancer disorders (see for example, Adjei et al. J Clin Oncol 2008 26(13):2139-2146; Board et al. Br J Cancer 2009 101(10):1724-30; Kolb et al. Pediatr Blood Cancer 2010 55(4):668-677). To Applicant's knowledge, these molecules have never been described for their use in treating spinal muscular atrophy or related disorders.
Thus, it is of the merit of the inventors to have provided new data showing that the pharmacological inhibition of ERK pathway, notably through the use of Selumetinib or related ERK inhibitors, could be an efficient treatment to alleviate SMA symptoms or related disorders associated to SMN deficiency resulting in loss of motor function in patients.